S100A9 is a functional effector of infarct wall thinning after myocardial infarction

Neutrophils infiltrate into the left ventricle (LV) early after myocardial infarction (MI) and launch a pro-inflammatory response. Along with neutrophil infiltration, LV wall thinning due to cardiomyocyte necrosis also peaks at day 1 in the mouse model of MI. To understand the correlation, we examined a previously published dataset that included day 0 (n=10) and MI day 1 (n=10) neutrophil proteome and echocardiography assessments. Out of 123 proteins, 4 proteins positively correlated with the infarct wall thinning index (1/wall thickness): histone 1.2 (r=0.62, p=0.004), S100A9 (r=0.60, p=0.005), histone 3.1 (r=0.55, p=0.01), and fibrinogen (r=0.47, p=0.04). As S100A9 was the highest ranked secreted protein, we hypothesized that S100A9 is a functional effector of infarct wall thinning. We exogenously administered S100A8/A9 at the time of MI to mice (C57BL/6J, male, 3-6 months of age, n=7M (D1), and n=5M (D3)) and compared to saline vehicle control treated mice (n=6M (D1) and n=6M (D3)) at MI days 1 and 3. At MI day 3, the S100A8/A9 group showed a 22% increase in the wall thinning index compared to saline (p=0.02), along with higher dilation and lower ejection fraction. The decline in cardiac physiology occurred subsequent to increased neutrophil and macrophage infiltration at MI day 1 and increased macrophage infiltration at D3. Our results reveal that S100A9 is a functional effector of infarct wall thinning.

A Single Center Experience with Early Adoption of Physiologic Pacing Approaches

Background: Increasing interest in physiological pacing has been countered with challenges such as accurate lead deployment and increasing pacing thresholds with His-bundle pacing (HBP). More recently, left bundle branch area pacing (LBBAP) has emerged as an alternative approach to physiologic pacing. Objective: To compare procedural outcomes and pacing parameters at follow-up during initial adoption of HBP and LBBAP at a single center. Methods: Retrospective review, from September 2016 to January 2020, identified the first 50 patients each who underwent successful HBP or LBBAP. Pacing parameters were then assessed at first follow-up after implantation and after approximately one year, evaluating for acceptable pacing parameters defined as sensing R-wave amplitude >5 mV, threshold <2.5 V @ 0.5 ms and impedance between 400 and 1200 Ohms. Results: The HBP group was younger with lower ejection fraction compared to LBBP (73.2±15.3 vs 78.2±9.2 years, p=0.047; 51.0±15.9% vs 57.0±13.1%, p = 0.044). Post-procedural QRS widths were similarly narrow (119.8±21.2 vs. 116.7±15.2ms; p = 0.443) in both groups. Significantly fewer patients with HBP met the outcome for acceptable pacing parameters at initial follow-up (56.0% vs 96.4%, p = 0.001) and most recent follow-up (60.7% vs 94.9%, p = <0.001; at 399±259 vs. 228±124 days, p = <0.001). More HBP patients required lead revision due to early battery depletion (0 vs 13.3%, at an average of 664 days). Conclusion: During initial adoption, as compared with LBBAP, HBP is associated with a significantly higher frequency of unacceptable pacing parameters, energy consumption, and lead revisions.

The Relationship between Serum Uric Acid and Ejection Fraction of the Left Ventricle

Study basis: As a byproduct of protein metabolism, serum uric acid is a controversial risk factor and is the focus of several recent studies in the field of cardiovascular disease. Whether serum uric acid is involved in the development of these pathologies alone or in conjunction with other factors is a matter of debate. Objective: The objective of this study is to assess the direct relationship between serum uric acid and the ejection fraction. Methods: A retrospective study of 303 patients with heart failure, classified according to the ESC guidelines, was conducted, and several parameters, along with the relationship between serum uric acid and ejection fraction, were characterized. Results: A direct relationship between the level of serum uric acid and the ejection fraction was established (p = 0.03); patients with higher uric acid had an increased risk of having a lower ejection fraction. Conclusions: Serum uric acid, even when asymptomatic, is linked with the level of the ejection fraction of the left ventricle.

Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction After a Recent Worsening Heart Failure Event

Background Contemporary trials of patients with heart failure with reduced ejection fraction (HFrEF) required a recent worsening heart failure (WHF) event for inclusion. We aimed to describe characteristics and outcomes of patients with HFrEF and a recent WHF event at a large tertiary referral center. Methods and Results We identified adult patients with chronic symptomatic HFrEF (ejection fraction ≤35%) treated at Duke University between January 1, 2009, and December 31, 2018, and applied a set of exclusion criteria to generate a cohort similar to those enrolled in contemporary heart failure trials. Patients were stratified by presence or absence of a recent WHF event, defined as an emergency department visit for heart failure or hospitalization for heart failure in the prior 12 months. Characteristics and outcomes including death and hospitalization were assessed. Of 3867 patients with HFrEF meeting study criteria, 2823 (73.0%) had a WHF event in the prior 12 months. Compared with patients without a WHF event, those with a WHF event were more likely to be under‐represented racial and ethnic groups and had lower ejection fraction, a greater burden of comorbidities, and more echocardiographic evidence of cardiac dysfunction. Despite higher use of guideline‐directed therapies, patients with a WHF event had higher rates of death (hazard ratio, 2.30; 95% CI, 2.01–2.63), all‐cause hospitalization (hazard ratio, 1.56; 95% CI, 1.42–1.71), and heart failure hospitalization (hazard ratio, 1.59; 95% CI, 1.44–1.75) through 5 years compared with those without a recent WHF event. Conclusions WHF events are common in patients with HFrEF and are associated with more advanced disease. Patients with recent WHF have high rates of death and hospitalization, underscoring the need for novel therapies in this large subgroup of patients with HFrEF.

Abstract 14327: Tricuspid Valve Annular Area Correlations and Determinants in Healthy Controls and Patients With Severe Mitral Regurgitation

Introduction: Concomitant tricuspid valve (TV) repair during mitral valve (MV) surgery based on annular dilation rather than the degree of regurgitation (TR) has been shown to be beneficial and is supported by the guidelines. Hypothesis: Assess the correlations between tricuspid and mitral annular areas (TVA and MVA, respectively) indexed to body surface area (BSA) measured by cardiac computed tomography (CT), and identify the determinants of the TVA in normal and diseased states. Methods: We included 50 consecutive controls (no valvular heart disease undergoing coronary CTA), 50 primary mitral regurgitation (PMR) patients referred for robotic repair, and 25 functional MR (FMR) patients referred for percutaneous therapy, without significant associated TR (≤2+ TR). We used dedicated CT software (Aquarius, TeraRecon) to perform the annular measurements. A mid-diastolic phase acquisition (~70%) was used Results: Patients with FMR were older (median age [25th, 75th] = 70 years [63,77.5] vs. 55 [48,59] in PMR and 48 [38,55] in controls), had more clinical comorbidities, and lower ejection fraction (32% [23,40] vs. >60% in both other groups). TVA was significantly correlated to MVA in controls (r≥0.5; p<0.001), as well as in patients with PMR and FMR. (Figure 1). Table 1 shows the univariate correlations and multivariate determinants of the TVA. In the multivariate analysis, the MVA, RA area, and LVEDV were the independent predictors of TVA. Interestingly, the MVA was the most important predictor (β= 0.420, p<0.001). Conclusion: In individuals without valvular heart disease and in patients with severe MR (PMR and FMR) with ≤ 2+ TR, the TVA was largely determined by the MVA.

The Effects of Neuropeptide Y Overexpression on the Mouse Model of Doxorubicin-Induced Cardiotoxicity

Doxorubicin is a potent anticancer drug with cardiotoxicity hampering its use. Neuropeptide Y (NPY) is the most abundant neuropeptide in the heart and a co-transmitter of the sympathetic nervous system that plays a role in cardiac diseases. The aim of this work was to study the impact of NPY on doxorubicin-induced cardiotoxicity. Transgenic mice overexpressing NPY in noradrenergic neurons (NPY-OEDβH) and wild-type mice were treated with a single dose of doxorubicin. Doxorubicin caused cardiotoxicity in both genotypes as demonstrated by decreased weight gain, tendency to reduced ejection fraction, and changes in the expression of several genes relevant to cardiac pathology. Doxorubicin resulted in a tendency to lower ejection fraction in NPY-OEDβH mice more than in wild-type mice. In addition, gain in the whole body lean mass gain was decreased only in NPY-OEDβH mice, suggesting a more severe impact of doxorubicin in this genotype. The effects of doxorubicin on genes expressed in the heart were similar between NPY-OEDβH and wild-type mice. The results demonstrate that doxorubicin at a relatively low dose caused significant cardiotoxicity. There were differences between NPY-OEDβH and wild-type mice in their responses to doxorubicin that suggest NPY to increase susceptibility to cardiotoxicity. This may point to the therapeutic implications as suggested for NPY system in other cardiovascular diseases.

Impact of Late Ventricular Arrhythmias on Cardiac Mortality in Patients with Acute Myocardial Infarction

Objectives. This study investigated the relationship between the timing of ventricular tachycardia or ventricular fibrillation (VT or VF) and prognosis in patients undergoing primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). Background. It is unknown whether the timing of VT/VF occurrence affects the prognosis of patients with AMI. Methods. From January 2004 to December 2014, 1004 patients with AMI underwent primary PCI. Of these patients, 888 did not have VT/VF (non-VT/VF group) and 116 had sustained VT/VF during prehospitalization or hospitalization. Patients with VT/VF were divided into two groups: early VT/VF (VT/VF occurrence before and within 2 days of admission, 92 patients) and late VT/VF (VT/VF occurrence >2 days after admission; 24 patients) groups. Results. The frequency of VT/VF occurrence was high between the day of admission and the 2nd day and between days 6 and 10 of hospitalization. The late VT/VF group had a significantly longer onset-to-balloon time, lower ejection fraction, poorer renal function, and higher creatine phosphokinase (CK)-MB level on admission (p< 0.001). They also had a lower 30-day cardiac survival rate than the early VT/VF and non-VT/VF groups (42% vs. 76% vs. 96%, p < 0.001). Moreover, independent predictors of in-hospital cardiac mortality among patients with AMI who had sustained VT/VF were higher peak CK-MB [Odds ratio (OR: 1.001, 95%confidence interval (CI): 1.000-1.002, p= 0.03)], higher Killip class (OR: 1.484, 95%CI 1.017-2.165, p= 0.04), and late VT/VF (OR: 3.436, 95%CI 1.115-10.59, p= 0.03). Conclusions. The timing of VT/VF occurrences had a bimodal peak. Although late VT/VF occurrence after primary PCI was less frequent than early VT/VF occurrence, patients with late VT/VF had a very poor prognosis.

Multidisciplinary transcatheter aortic valve replacement heart team programme improves mortality in aortic stenosis

ObjectivesTo analyse the effect of the implementation of a transcatheter aortic valve replacement (TAVR) and multidisciplinary heart team programme on mortality in severe aortic stenosis (AS).MethodsA retrospective, observational cohort study was performed using the echocardiography, cardiothoracic surgery and TAVR databases between 1 January 2006 and 31 December 2016. Outcomes were compared between the pre- and post-TAVR programme eras in a tertiary referral centre providing transcatheter and surgical interventions for AS.All-cause mortality within 5 years from diagnosis was determined for 3399 patients with echocardiographically defined severe AS.ResultsOf 3399 patients, there were 210 deaths (6.2%) at 30 days and 1614 deaths (47.5%) at 5 years.Overall, patients diagnosed in the post-TAVR programme era were older, with a lower ejection fraction and more severe AS, but were less comorbid.Among 705 patients undergoing intervention, those in the post-TAVR programme era were older, with a lower ejection fraction and more severe AS but no significant differences in comorbidities.Using an inverse probability weighted cohort and a Cox proportional hazards model, a significant mortality benefit was noted between eras alone (HR=0.86, 95% CI 0.77 to 0.97, p=0.015). When matching for age, comorbidities and valve severity, this benefit was more evident (HR=0.82, 95% CI 0.73 to 0.92, p=0.001).After adjusting for the presence of aortic valve intervention, a significant benefit persisted (HR=0.84, 95% CI 0.75 to 0.95, p=0.005).ConclusionThe implementation of a TAVR programme is associated with a mortality benefit in the population with severe AS, independent of the expansion of access to intervention.